The invention provides compounds having selective (programmed) stability in adverse chemical and dynamic biologic environments. The disclosed compounds permit selective control of the extent and rate of conversion of the inventive compounds to a hydroxyl-substituted chiral xanthine compound.
Drugs possessing a chiral center generally are developed, tested, manufactured and marketed as racemates, containing equivalent amounts of each respective enantiomer. In biologic systems, one enantiomer may be an active compound while the other enantiomer may have little or no effect. Therefore in some instances, skilled artisans may seek to enhance efficacy, improve potency or prolong therapeutic potential by isolating efficacious enantiomers from nonactive ones.
Enantiomerically pure compounds have been prepared by first synthesizing a racemate, and then, using chiral separation techniques, isolating the enantiomers. Manufacturing and dosing drugs as racemic mixtures means that each drug dose contains an equivalent amount of a corresponding isomer, sometimes having little or no therapeutic potential and quite possibly may cause unsuspected and undesirable side affects.
Thus, in many biologic systems, to attain, inter alia, greater potency or prolonged efficacy of compounds in the laboratory, a need exists to administer substantially pure enantiomers for use as pharmaceuticals. An example of one such pure enantiomer is the compound lisofylline, 1-(5-(R)-hydroxyhexyl)-3,7-dimethylxanthine, (described in U.S. application Ser. No. 08/307,554 filed on Sep. 16, 1994 (now pending), the entire disclosure of which is incorporated by reference herein). Lisofylline is useful for a wide variety of therapeutic indications, including, for example, treating sepsis and sepsis syndrome, preventing multi-organ dysfunction associated with trauma, increasing the production of multilineage hematopoietic cells after cytoreductive therapies, promoting trilineage engraftment after bone marrow transplantation, and alleviating the toxic side effect of interleukin-2 (IL-2), amphotericin B, cyclosporin A, FK506 or granulocyte macrophage colony stimulating factor (GM-CSF) therapies.
In vitro and in vivo studies and human clinical trials with i.v. administered lisofylline confirm therapeutic efficacy of this substantially pure enantiomer. Further studies in predictive animal models (e.g., mouse, rat and dog models) using lisofylline as an oral formulation conclusively indicate that the chiral lisofylline is absorbed as a chiral molecule. Oral administration of a drug is often desired for, inter alia, ease of use, self-administered therapy and cost reduction; and thus, an orally administered drug, which eliminates more invasive i.v. and i.p. procedures is desirable.
In general, therapeutic deficiencies of new or existing drugs usually result from difficulties in any of three phases of drug action: pharmaceutic, biopharmaceutic, and pharmacodynamic. The pharmaceutic phase refers to the chemical and physical environment of a drug prior to its absorption into the living system and includes the dosage form of the drug as well as tissues encountered at the site of administration. The biopharmaceutic phase of drug action include absorption, distribution, biotransformation, and elimination of the drug. The pharmacodynamic phase deals with the drug at its pharmacologic site(s) of action. Difficulty associated with any of these three phases of drug action can result in either a subtherapeutic or toxic response of the patient to drug therapy. Riley, T. N., xe2x80x9cThe Concept and New Drug Design and Development,xe2x80x9d Journal of Chemical Education, Vol. 65 No. 11, pages 947-953, November 1988.
In orally administered, enantiomerically pure pharmaceuticals, a compound must retain its efficacious properties and chemical and chiral structure throughout various degrative biologic systems enroute to the bloodstream after ingestion. Such systems, which are encountered enroute to merging with systemic blood flow include, for example, digestion (stomach gastric juices), metabolism (intestinal membrane, portal vein and liver blood) and blood filtration (kidney and especially liver). Skilled artisans strive to minimize a first pass effect. The first pass effect is defined as those processes, such as digestion, metabolism and blood filtration which alter the drug such that it becomes inactive. An objective in minimizing the first pass effect is to increase bioavailability of orally administered pharmaceutical compounds. An increased systemic concentration of a therapeutic compound for a longer period of time corresponds to higher bioavailability.
A prodrug is defined as a pharmacologic precursor (parent) to an active compound, which itself alone may possess efficacious properties. Conversion of a prodrug to an active compound occurs by either chemical or enzymatic processes after administration. Riley, supra. Altering the chemical structure of a compound may include modification of structural features requiring sophisticated chemical or biochemical mechanisms to generate the parent specie.
The preparation of a xe2x80x9cprodrugxe2x80x9d form of another compound can have a number of beneficial effects in terms of increasing therapeutic utility of the therapeutic compound. Such beneficial effects include, for example, improved chemical stability characteristics, improved absorption characteristics following oral administration, better taste to improve patient compliance upon oral administration, and improved pharmacodynamics and pharmacokinetic characteristics, including altering metabolism of the parent chiral drug.
Target compounds as prodrug candidates must be stable in a variety of chemical and biologic systems, including the gastrointestinal tract and whole blood so as to have maximum effect on increasing bioavailability of an intended -pharmaceutical in vivo. Yet, these candidates need not liberate a parent compound quickly or completely prior to or during ingestion or in the liver to achieve this result, and often it is undesirable to do so.
Because of the complexity of some biologic systems and the specificity of compounds as they relate to particular chemical or enzymatic pathways, success of one prodrug approach is not conclusive of proof of success for other drugs having differing structures and targeted therapeutic potential. Problems with solubility, toxicity, stability, bioavailability all vary between drugs. Bundgaard et al., xe2x80x9cA Novel Solution-Stable, Water-Soluble Prodrug Type for Drugs Containing a Hydroxyl or an NH-Acidic Group,xe2x80x9d Journal of Medicinal Chemistry, Vol. 32, No. 12, pages 2503-2507, December 1989.
Hussain et al. disclose selected prodrugs of Naltrexone, used in treating opioid addiction. xe2x80x9cImprovement of the Oral Bioavailability of Naltrexone in Dogs: A Prodrug Approach,xe2x80x9d Journal or Pharmaceutical Sciences, Vol. 76, No. 5, pages 356-358, May 1987. The disclosed prodrugs include anthranilate, acetylsalicylate, benzoate and pivalate esters of Naltrexone. Naltrexone has numerous chiral centers, but Hussain et al. were concerned only with bioavailability of the racemic compound. Of the four esters disclosed, only the anthranilate and acetylsalicylate esters exhibited substantially higher bioavailability when compared with the bioavailability for orally administered Naltrexone. But, as acknowledged by Hussain et al., there is no correlation between bioavailability and the in vitro hydrolysis half-life. Thus, identifying and isolating a prodrug having the necessary characteristics to minimize or eliminate the first pass effect is a difficult task. In particular, lisofylline, its efficacious properties primarily a result of its specific enantiomeric stereochemistry, made a search for a corresponding oral prodrug of lisofylline very difficult.
The invention is in response to an identified need to develop compounds that have selective stability in adverse chemical and metabolic systems. Such compounds would ideally be capable of maintaining enantiomeric stereochemistry, but when exposed to an adverse chemical or biologic environment (whether in vitro or in vivo), would maintain their chemical properties, having their own efficacious properties, or could be converted to a corresponding therapeutic compound. The invention results from these efforts to discover compounds, heretofore unknown, which structurally would have not only specific, variable abilities to maintain enantiomeric chemistry, but also programmed stability in dynamic, metabolic systems.
The inventive compounds possess varying stabilities and different rates of hydrolysis to a corresponding alcohol. Such differences correlate to programmed hydrolytic potential. These differences are characteristic of varying chemical structures and thus programmed rates of hydrolysis are compound specific. More particularly, the invention provides a compound comprising a xanthine core of the formula I or a pharmaceutically acceptable salt, solvate or hydrate thereof: 
One of R1 or R2 is independently an aliphatic hydrocarbon having the formula II: 
In formula II, n is an integer from about four to about eight, R1 or R2, which is other than formula II, and R3 are independently C(1-12) alkyl and C* is a chiral carbon atom. R4 is an amino acid or carbohydrate attached to the chiral carbon atom C* via an ester linkage, or xe2x80x94Oxe2x80x94Xxe2x80x94(R5)m.
If R4 is xe2x80x94Oxe2x80x94Xxe2x80x94(R5)m, m is two or three, X is selected from the group consisting of C, P or S and R5 is a hydrogen atom; hydroxyl group; xe2x95x90O; substituted or unsubstituted C(1-10) alkyl, C(1-10) alkenyl, C(1-10) alkynyl, C(1-10) alkoxyl, C(1-10) oxoalkyl, or C(1-10) acetoxyl, C(1-10) carboxyalkyl, or C(1-10) hydroxyalkyl group; xe2x80x94OR6, R6 being a substituted or unsubstituted C(1-10) alkyl, C(1-10) alkenyl, C(1-10) alkynyl; C(1-10) oxoalkyl; substituted or unsubstituted cyclic or heterocylic group having from one- to three-rings, each ring containing from four to seven atoms.
These chiral inventive compounds provide for selectively stable compounds, both in vitro and in vivo. In more preferred compounds of the invention, a specific moiety chirally linked to the lisofylline skeleton permits control of the extent and rate of conversion of the inventive compounds to a corresponding alcohol. An acidic or basic environment, or when administered orally, various intestinal enzymes, or plasma or liver enzymes, hydrolyze the inventive compounds to form a corresponding alcohol. Thus, the present invention provides, inter alia, prodrugs for active chiral secondary xcfx89-1 hydroxyl-substituted xanthine compounds.